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Imidazoacridone

C-1311 is a member of the novel imidazoacridinone family of anticancer agents.  In a phase trial, twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m(2). All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m(2), with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. CONCLUSION: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound. see http://www.ncbi.nlm.nih.gov/pubmed/20031390.  

Current developer:   Politechnika Gdanska (Originator), BTG (Licensee),
Xanthus Pharmaceuticals Inc(Licensee).

 1: Isambert N, Campone M, Bourbouloux E, Drouin M, Major A, Yin W, Loadman P, Capizzi R, Grieshaber C, Fumoleau P. Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours. Eur J Cancer. 2010 Mar;46(4):729-34. Epub 2009 Dec 22. PubMed PMID: 20031390.

2: Mayur YC, Peters GJ, Prasad VV, Lemo C, Sathish NK. Design of new drug molecules to be used in reversing multidrug resistance in cancer cells. Curr Cancer Drug Targets. 2009 May;9(3):298-306. Review. PubMed PMID: 19442050.

3: Bram EE, Adar Y, Mesika N, Sabisz M, Skladanowski A, Assaraf YG. Structural determinants of imidazoacridinones facilitating antitumor activity are crucial for substrate recognition by ABCG2. Mol Pharmacol. 2009 May;75(5):1149-59. Epub 2009 Feb 27. PubMed PMID: 19251825.

4: Kowalczyk A, Nowicka AM, Karbarz M, Stojek Z. Thermoresponsive polymeric gel as a medium for examining interactions between dsDNA and an anticancer drug. Anal Bioanal Chem. 2008 Oct;392(3):463-9. Epub 2008 Aug 21. PubMed PMID: 18716762.

5: Wiśniewska A, Chrapkowska A, Kot-Wasik A, Konopa J, Mazerska Z. Metabolic transformations of antitumor imidazoacridinone, C-1311, with microsomal fractions of rat and human liver. Acta Biochim Pol. 2007;54(4):831-8. Epub 2007 Dec 17. PubMed PMID: 18084652.

6: Alami N, Paterson J, Belanger S, Juste S, Grieshaber CK, Leyland-Jones B. Comparative cytotoxicity of C-1311 in colon cancer in vitro and in vivo using the hollow fiber assay. J Chemother. 2007 Oct;19(5):546-53. PubMed PMID: 18073154.

7: Friedrich J, Eder W, Castaneda J, Doss M, Huber E, Ebner R, Kunz-Schughart LA. A reliable tool to determine cell viability in complex 3-d culture: the acid phosphatase assay. J Biomol Screen. 2007 Oct;12(7):925-37. Erratum in: J Biomol Screen. 2007 Dec;12(8):1115-9. PubMed PMID: 17942785.

8: Nowicka AM, Zabost E, Donten M, Mazerska Z, Stojek Z. Electroanalytical and spectroscopic procedures for examination of interactions between double stranded DNA and intercalating drugs. Anal Bioanal Chem. 2007 Nov;389(6):1931-40. Epub 2007 Oct 17. PubMed PMID: 17940754.

9: Skwarska A, Augustin E, Konopa J. Sequential induction of mitotic catastrophe followed by apoptosis in human leukemia MOLT4 cells by imidazoacridinone C-1311. Apoptosis. 2007 Dec;12(12):2245-57. PubMed PMID: 17924195.

10: De Marco C, Zaffaroni N, Comijn E, Tesei A, Zoli W, Peters GJ. Comparative evaluation of C1311 cytotoxic activity and interference with cell cycle progression in a panel of human solid tumour and leukaemia cell lines. Int J Oncol. 2007 Oct;31(4):907-13. PubMed PMID: 17786324.

11: Bram EE, Ifergan I, Grimberg M, Lemke K, Skladanowski A, Assaraf YG. C421 allele-specific ABCG2 gene amplification confers resistance to the antitumor triazoloacridone C-1305 in human lung cancer cells. Biochem Pharmacol. 2007 Jun 30;74(1):41-53. Epub 2007 Apr 1. PubMed PMID: 17481587.

12: Suggitt M, Cooper PA, Shnyder SD, Bibby MC. The hollow fibre model--facilitating anti-cancer pre-clinical pharmacodynamics and improving animal welfare. Int J Oncol. 2006 Dec;29(6):1493-9. PubMed PMID: 17088988.

13: den Brok MW, Nuijen B, Harms R, Buluran JN, Harvey MD, Grieshaber CK, Beijnen JH. Compatibility and stability of the novel anti-cancer agent C1311 in infusion devices and its in vitro biocompatibility. J Oncol Pharm Pract. 2005 Mar;11(1):13-9. PubMed PMID: 16460599.

14: Den Brok MW, Nuijen B, Kettenes-Van Den Bosch JJ, Van Steenbergen MJ, Buluran JN, Harvey MD, Grieshaber CK, Beijnen JH. Pharmaceutical development of a parenteral lyophilised dosage form for the novel anticancer agent C1311. PDA J Pharm Sci Technol. 2005 Sep-Oct;59(5):285-97. PubMed PMID: 16316064.

15: den Brok MW, Nuijen B, Hillebrand MJ, Grieshaber CK, Harvey MD, Beijnen JH. Development and validation of an LC-UV method for the quantification and purity determination of the novel anticancer agent C1311 and its pharmaceutical dosage form. J Pharm Biomed Anal. 2005 Sep 1;39(1-2):46-53. PubMed PMID: 15899571.

16: Hyzy M, Bozko P, Konopa J, Skladanowski A. Antitumour imidazoacridone C-1311 induces cell death by mitotic catastrophe in human colon carcinoma cells. Biochem Pharmacol. 2005 Mar 1;69(5):801-9. Epub 2005 Jan 18. PubMed PMID: 15710357.

17: Mazerska Z, Sowiński P, Konopa J. Molecular mechanism of the enzymatic oxidation investigated for imidazoacridinone antitumor drug, C-1311. Biochem Pharmacol. 2003 Nov 1;66(9):1727-36. PubMed PMID: 14563483.

18: Mazerska Z. Similarity between enzymatic and electrochemical oxidation of 2-hydroxyacridinone, the reference compound of antitumor imidazoacridinones. Acta Biochim Pol. 2003;50(2):515-25. PubMed PMID: 12833176.

19: Dziegielewski J, Slusarski B, Konitz A, Skladanowski A, Konopa J. Intercalation of imidazoacridinones to DNA and its relevance to cytotoxic and antitumor activity. Biochem Pharmacol. 2002 May 1;63(9):1653-62. PubMed PMID: 12007568.

20: Zaffaroni N, De Marco C, Villa R, Riboldi S, Daidone MG, Double JA. Cell growth inhibition, G2M cell cycle arrest and apoptosis induced by the imidazoacridinone C1311 in human tumour cell lines. Eur J Cancer. 2001 Oct;37(15):1953-62. PubMed PMID: 11576853.

21: Mazerska Z, Dziegielewski J, Konopa J. Enzymatic activation of a new antitumour drug, 5-diethylaminoethylamino-8-hydroxyimidazoacridinone, C-1311, observed after its intercalation into DNA. Biochem Pharmacol. 2001 Mar 15;61(6):685-94. PubMed PMID: 11266653.

22: Burger AM, Jenkins TC, Double JA, Bibby MC. Cellular uptake, cytotoxicity and DNA-binding studies of the novel imidazoacridinone antineoplastic agent C1311. Br J Cancer. 1999 Sep;81(2):367-75. PubMed PMID: 10496367; PubMed Central PMCID: PMC2362878.

23: Calabrese CR, Loadman PM, Lim LS, Bibby MC, Double JA, Brown JE, Lamb JH. In vivo metabolism of the antitumor imidazoacridinone C1311 in the mouse and in vitro comparison with humans. Drug Metab Dispos. 1999 Feb;27(2):240-5. PubMed PMID: 9929509.

24: Calabrese CR, Bibby MC, Double JA, Loadman PM. Pharmacokinetics and tissue distribution of the imidazoacridinone C1311 in tumour-bearing mice. Cancer Chemother Pharmacol. 1998;42(5):379-85. PubMed PMID: 9771952.

25: Jóźwiak Z, Pacholska M, Szwarocka A. The effects of imidazoacridinones, new antineoplastic agents, on the human erythrocyte membrane. Biochem Mol Biol Int. 1997 Nov;43(4):883-90. PubMed PMID: 9385448.

26: Calabrese CR, Loadman PM. Analysis of the imidazoacridinone C1311 by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1997 Mar 7;690(1-2):275-81. PubMed PMID: 9106053.

27: Burger AM, Double JA, Konopa J, Bibby MC. Preclinical evaluation of novel imidazoacridinone derivatives with potent activity against experimental colorectal cancer. Br J Cancer. 1996 Nov;74(9):1369-74. PubMed PMID: 8912531; PubMed Central PMCID: PMC2074789.

28: Lamb J, Wheatley DN. Cell killing by the novel imidazoacridinone antineoplastic agent, C-1311, is inhibited at high concentrations coincident with dose-differentiated cell cycle perturbation. Br J Cancer. 1996 Nov;74(9):1359-68. PubMed PMID: 8912530; PubMed Central PMCID: PMC2074775.

29: Skladanowski A, Plisov SY, Konopa J, Larsen AK. Inhibition of DNA topoisomerase II by imidazoacridinones, new antineoplastic agents with strong activity against solid tumors. Mol Pharmacol. 1996 May;49(5):772-80. PubMed PMID: 8622625.

30: Berger B, Marquardt H, Westendorf J. Pharmacological and toxicological aspects of new imidazoacridinone antitumor agents. Cancer Res. 1996 May 1;56(9):2094-104. PubMed PMID: 8616856.

31: Augustin E, Wheatley DN, Lamb J, Konopa J. Imidazoacridinones arrest cell-cycle progression in the G2 phase of L1210 cells. Cancer Chemother Pharmacol. 1996;38(1):39-44. PubMed PMID: 8603450.